Erythropoietin (EPO) plays a central role in regulating erythroid development and recombinant EPO is widely used in patients to treat erythropoietic insufficiency. However, very little is known about the effect of EPO on non-erythroid cells. We recently found that Salmonella infection induces EPO production and erythroid expansion and that this has a beneficial effect on bacterial growth in vivo. Together, these data suggest a surprising level of crosstalk between the immune response to bacterial infection and the homeostatic regulation of erythroid development. Our goal in this exploratory application is to study this important new research area in more detail. Given the novelty and potential importance of erythroid-immune interactions, we believe greater understanding of this area could lead to the generation of new vaccines and therapeutics for bacterial infections. Our application specifically proposes to, (i) identify the cell population and bacterial products responsible for EPO production during infection, and (ii) examine whether EPO has direct and indirect effects on the immune response to infection. Overall, our proposal bridges two well-developed, but disconnected, research fields and is likely to have broader implications for understanding how erythroid development impacts immune responses to infectious disease. PUBLIC HEALTH RELEVANCE: Typhoid fever is found in geographical areas that lack clean water or basic sanitation, and affects 27.1 million people and causes 217,000 deaths annually. Splenomegaly is a prominent feature of this infection and we recently found that this is caused by expansion of erythroid progenitor cells and is advantageous for bacterial growth. Our goal in this exploratory application is to define bacterial products and cell populations that give rise to elevated EPO production and examine the effect of EPO on the innate and adaptive immune response. Given the novelty of erythroid-immune interactions, we believe greater understanding of this area could lead to the generation of new vaccines and therapeutics for bacterial infections.